Infection is an increasingly serious problem to public health, from intensive care units (ICUs), to trauma and wound infection, to infections among the immune compromised. Infection is associated with unacceptable morbidity, mortality, and cost. According to the results of the recent EPIC II studies, infected patients have much higher hospital mortality rates, up to 33.1% versus 14.8% for non-infected patients. Despite the recent media attention focused on methicillin-resistant Staphylococcus aureus (MRSA), the looming threat in MDR pathogens over the last decade has increasingly been the rise of Gram-negative pathogens Pseudomonas aeurginosa (PA) or Acinetobacter baumannii (AB).
Such pathogens are isolated in 62% of patients in ICU settings, versus 47% for Gram-positive pathogens. Pseudomonas aeruginosa is one of the most common life-threatening pathogens in public health, particularly among immune compromised or immune suppressed patients. Infections caused by multi-drug-resistant Pseudomonas aeurginosa (MDRPA) can occur in any person, including hospital acquired pneumonia, catheter-associated infections and bacteremia, sepsis, respiratory infections, penetrating, crushing, or wound infections, and community-acquired infections of the eyes, ears, or sinuses from waterborne sources. Recent, population-based data of nosocomial infections caused by MDRPA in Europe identified an incidence of 126 cases per 100,000 individuals.
Likewise, multi-drug-resistant Acinetobacter baumannii (MDRAB) is an increasingly urgent and unaddressed pathogen responsible for life-threatening infections, particularly in ICU settings, including ventilator associated pneumonia, bacteremia, surgical site infection, and sepsis. Treating such infections caused by MDRAB is difficult due to resistance to multiple antibiotics, including carbapenems, and attributable mortality rates are high.
Infections caused by MDRPA and MDRAB are virtually always resistant to many classes of antibiotics, and commonly resistant all antibiotics in the medical formulary. Thus, there are increasing reports of truly pan-resistant infections due to these organisms which cannot be treated with any available antibiotic or combination.
Correlating with a highly antibiotic-resistant nature, infections caused by MDRPA or MDRAB are associated with high mortality rates. For example, MDRPA is associated with increased risk of mortality from sepsis, and is a significant predictor of ICU mortality. Finally, there is a concerning absence of new antibiotics or those in development that have novel mechanisms of action against these agents. For example, even a recently approved antibiotic, tigecycline, is inactive vs. MDRPA. Of greater concern, few if any antibiotics currently in phase II or later clinical trials has improved efficacy against MDRPA or MDRAB as compared with existing agents. These alarming trends underscore the desperate need for new strategies to treat antibiotic-resistant and deadly Gram-negative infections.
Another wide-spread infectious disease is malaria. Uncomplicated malaria may be treated with oral medications. The current treatment for P. falciparum infection is the use of artemisinins in combination with other antimalarials (known as artemisinin-combination therapy, or ACT), which may decrease resistance to any single drug component. These additional antimalarials include: amodiaquine, lumefantrine, mefloquine or sulfadoxine/pyrimethamine. Another recommended combination is dihydroartemisinin and piperaquine. ACT is about 90% effective when used to treat uncomplicated malaria. Infection with P. vivax, P. ovale or P. malariae is usually treated without the need for hospitalization. Treatment of P. vivax requires both treatment of blood stages (with chloroquine or ACT) and clearance of liver forms with primaquine. Recommended treatment for severe malaria is the intravenous use of antimalarial drugs. For severe malaria, artesunate is superior to quinine in both children and adults.
Despite potential benefits of combination therapy, drug resistance to various malaria treatments poses a growing problem in the 21st-century. Resistance is now common against all classes of antimalarial drugs apart from artemisinins. Treatment of resistant strains became increasingly dependent on this class of drugs. The cost of artemisinins limits their use in the developing world. Malaria strains found on the Cambodia-Thailand border are resistant to combination therapies that include artemisinins, and may therefore be untreatable. Exposure of the parasite population to artemisinin monotherapies in subtherapeutic doses for over 30 years and the availability of substandard artemisinins likely drove the selection of the resistant phenotype.